Abstract
Abstract Cellular metabolism sits at the forefront of growth and has been identified as an essential element for the progression of cancer. Large-scale chromosomal alterations and mutations incurred by cancerous cells can predispose cancer cells to dysfunctional metabolic programming independent of microenvironmental pressure. Cancer cells are adaptable to this reprogramming and find alternative measures to sustain elevated metabolic demands. However, this process reduces the number of functional metabolic pathways. Dysregulated metabolic pathways within cancerous cells create an opportunity for therapeutic intervention by targeting genetic chokepoints within these pathways. We analyzed metabolic landscape of breast cancers by combining genomic and transcriptomic data from cancer patient datasets, to identify metabolic pathways prone to dysregulation due to genomic influence. Our platform identified disruption in the serine biosynthesis, which some cancerous cells rely upon to sustain elevated growth in a subset of breast carcinoma. We utilized gain- and loss-of-function techniques in multiple breast cancer cell lines to recapitulate metabolic disruption observed in tumors. These in vitro screens are complemented by metabolic flux analysis and stable-isotope tracer analysis that reveal the vulnerable metabolic pathways in breast cancers with dysregulated serine metabolism. Our data demonstrate that specific metabolic targets can be identified through this integrated screening and validated empirically to confirm their significance as avenues for potential therapeutics. Citation Format: Mark Daniel Slayton, Abhinav Achreja, Jin Heon Jeon, Liwei Bao, Alisa Liu, Mason Collard, Deepak Nagrath, Sofia Merajver. Integrated in vitro and in silico screening of breast cancer reveals serine metabolism as a precision oncology target [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3030.
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